Abstract: Cytokine activation of the Jak/Stat pathway is a key signaling network that controls many homeostatic programs required for development, differentiation and orchestrating responses to pathogens. Activation of sets of early response genes by the Stat transcription factors is a key endpoint for initiation of these numerous responses. We have made the observation that in addition to their actions as transcription factors some Stats regulate the transcription of mitochondria-encoded genes and ATP production. We hypothesize that mitochondria-localized transcription factors play an important role in adaptive responses to pathogens. Using mouse models this proposal will examine the physiological importance of Stat regulation of mitochondrial respiration.